Pre-bone Marrow Transplantation Research Articles

The Role of Pre-bone Marrow Transplantation Pulmonary Function Test in Predicting Post-transplant Noninfectious Pulmonary Complications

Background: Pulmonary function test (PFT) is used as a tool for pre-transplant risk assessment and as a predictor of post-transplant outcomes. As there are currently few studies that discuss the role of PFT in bone marrow transplantation (BMT) patients in Saudi settings, and as the number of transplant patients with benign and malignant conditions continues to increase, this study was conducted with the aim of assessing the local practice. Methods: This retrospective cohort study included all adult patients who underwent BMT at Princess Noorah Oncology Center, King Abdulaziz Medical City, Jeddah, between 2014 and 2020. The association between established patient-related risk factors and the incidence of pulmonary complications among autologous and allogeneic groups was assessed. Results: A total of 186 patients were included (autologous = 143; allogenic = 43), of which 115 (61.8%) were male. At the pre-BMT phase, about 30% of the patients had comorbidities and 51% had received two rounds of salvage chemotherapy, while 16.1% had received radiation therapy. In the autologous group, the only PFT parameter that was a significant predictor of post-BMT pulmonary complications was forced vital capacity <80% (P = 0.012), while in the allogenic group, no parameter was significantly associated with pulmonary complications. The patient-related factors that were associated with respiratory distress in the autologous group were lung involvement (P = 0.03) and pre-transplant radiation (P = 0.044). Conclusion: The findings of this study indicated that forced vital capacity <80% was a significant factor in predicting non-infectious complications in the autologous group. Furthermore, lung involvement and pre-transplant radiation were the patient-related factors associated with pulmonary complications.

Combining Flow Cytometry and Molecular Assessment Improves the Prognostic Value of Pre-Transplant Minimal Residual Disease in Acute Myeloid Leukemia

BACKGROUND AND AIMSAllogeneic bone marrow transplantation (BMT) offers the greatest chance of cure for high-risk acute myeloid leukemia (AML) patients. Persistence of disease or high levels of pre BMT minimal residual disease (MRD) have been reported to predict relapse risk after BMT. Multicolor flow cytometry (MFC) is the most common tool to evaluate MRD, whereas WT1 gene expression is the most widely applicable and standardized molecular MRD marker in AML. The aim of this study was to analyze the role of pre-BMT combined MFC-molecular MRD assessment as predictor for the post-transplant relapse risk.MATERIALS AND METHODSWe retrospectively analyzed the outcome of 224 consecutive AML patients receiving allo-BMT in 1st or 2nd CR. Pre-BMT marrow samples were analysed for WT1 expression and MFC as MRD evaluation. Median age at transplant was 44 years. Disease phase was CR1 in 161 (72%) and CR2 in 63 patients (28%). BMT conditioning wasmyeloablative in 163 (73%), whereas 61 patients (27%) received reduced intensity conditioning. Stem cell source was HLA-identical sibling in 79 (35%),haploidentical in 59 (27%) and alternative donor in 86 (38%).Median follow-up was 64 months (95% CI 50.3 - 77.3 months). Cumulative Incidence of Relapse (CI of relapse) at various time-points was calculated in competing risk analysis by takingin account non relapse mortality as competing event. Overall Survival (OS) was calculated from the time of BMT until death by any cause or last follow-up.A positive MFC MRD was defined by the presence of no less than 25 clustered leukemic cells/105 total events (threshold of 2.5x10-4 residual leukemic cells) at four-color flow-cytometry. WT1 copy number/Abl copy number 500x104 was used as cut-off value for abnormal WT1 expression.RESULTSRelapse occurred in 62 patients (27.7%). Three-year estimate of CI of relapse was 25.9% (median not reached). The CI of relapse was significantly affected by occurrence of acute GVHD (lower for grade ≥2, p <0.05) and MRD status before BMT, measured with any method (p <0.001 for WT1-based MRD, p<0.03 for MFC based MRD, p<0.0001 for combined MRD). In multivariate analysis the combined MRD evaluation and the onset ofaGVHDwere the only independent predictor of CI of relapse (p <0.001 and 0.04, respectively, Table I).Specifically, patients with double positive molecular and MFC MRD had a very poor outcome, with a 3-year CI of relapse of 51.9% (Figure 1). On the contrary, patients with negative combined MRD had a very low CI of relapse, regardless of the conditioning regimen received, whereas a trend toward benefit frommyeloablativeconditioning was observed in patients with MFC positive/WT1 negative MRD and double positive patients.Patients with negative MFC-MRD undergoing BMT in 1st or 2nd CR had a very similar outcome (3-year CI of relapse 8.3 and 5.6%, respectively). Similarly, MFC positive/WT1 negative MRD patients had a 3-year CI of relapse of 17.3 and 18.% for CR1 and CR2 patients, respectively. Patients who were MRD positive by both methods undergoing BMT in CR1 or CR2 had a similar, very high CI of relapse (Figure 2).MRD evaluation was also a strong predictor of long term survival: 3- years OS was 73.5% for MFC negative and 36.7% for double WT1 and MFC MRD positive patients, respectively, (p <0.001). Multivariate OS analysis showed that conditioning intensity and combined MRD evaluation significantly influenced OS duration (p <0.005 and <0.001, respectively)CONCLUSIONSPre transplant MRD evaluation by combined molecular and MFC assessment on bone marrow samples is a reliable predictor of relapse risk. Patients with both negative pre-BMT MRD markers have a significantly lower CI of relapse, while patients with both positive MRD markers display an higher risk of relapse. Given the high prognostic value, combined molecular/MFC pre-transplant MRD status may be taken in account when considering the most appropriate stem cell source or conditioning for each patient. Furthermore, identifying patient in morphological CR at BMT but with a very high risk of relapse, such as double positive patients, could open the way to apply pre-emptive therapeutic strategies to prevent AML relapse, from donor lymphocyte infusion to other innovative approaches. [Display omitted] [Display omitted] [Display omitted] DisclosuresGobbi:Janssen: Consultancy, Honoraria; Novartis: Consultancy, Research Funding; Celgene: Consultancy; Roche: Honoraria; Mundipharma: Consultancy, Research Funding; Takeda: Consultancy; Gilead: Honoraria.

High Predictive Value of Pre Transplant Minimal Residual Disease Assessment By Combining WT1 Expression and Flow Cytometry in Acute Myeloid Leukemia

BACKGROUND AND AIMSAllogeneic bone marrow transplantation (BMT) offers the greatest chance of cure for patients with high-risk acute myeloid leukemia (AML). Persistence of disease or high levels of pre BMT minimal residual disease (MRD) have been reported to predict relapse risk after BMT. WT1 expression levels and multicolor flow cytometry (MFC) are the most common tools to evaluate MRD. We recently reported that combining WT1 expression and MFC for MRD detection after induction therapy strongly impacts on relapse risk in AML. The aim of this study was to analyze the role of pre-BMT MRD assessment as predictor for the post-transplant relapse risk.MATERIALS AND METHODSWe retrospectively analyzed the outcome of 253 consecutive AML patients receiving allo-BMT. Pre-BMT marrow samples were analysed for WT1 expression and MFC as MRD evaluation . Median age at transplant was 45 years. Disease phase was CR1 in 161, CR2 in 63, and CR3 in 29 patients. One hundred eighty-two received myeloablative conditioning, whereas 71 patients received reduced intensity conditioning. Median follow-up was 59 months (95% CI 46.2 - 71.8 months). Relapse-free survival (RFS) was calculated from the time of transplantation until last follow-up or documented leukemic relapse. Overall Survival (OS) was calculated from the time of transplantation until death by any cause or last follow-up.A positive MFC MRD was defined by the presence of no less than 25 clustered leukemic cells/105 total events (threshold of 2.5x10-4 residual leukemic cells) at four-color flow-cytometry. Real-time PCR for WT1 was performed on DNA Engine 2 (Opticon®, MJ Research®). WT1 copy number/Abl copy number 500x104 was used as cut-off value for abnormal WT1 expression.RESULTSRelapse occurred in 81 patients (32%). Three-year estimate of RFS was 63.7% (median not reached). The probability of relapse was significantly affected by disease status (first or subsequent CR, p<0.01), occurrence of acute GVHD (grade 0-1 versus 2 or more, p <0.05), MRD status before transplantation, measured with any method (p <0.001 for WT1-based MRD, p<0.03 for MFC based MRD, p<0.0001 for combined MRD). Multivariate RFS analysis revealed that the combined MRD evaluation was the only independent predictor of RFS (p <0.001).Specifically, MFC-MRD was the strongest predictor of longer relapse free survival (p <0.001) since only two relapses occurred in the 25 MFC-MRD negative patients and 3-years RFS was 89.9%. Among MFC-MRD positive patients, WT1 MRD status stratified the risk of relapse as the 3-years RFS was 71.9% and 31.3%, respectively, for patients with normal or increase WT1, p <0.01, fig.1). The predictive value of MRD was independent from induction schedules, donor type, disease status at BMT and risk group, occurrence of acute or chronic GVHD. Similarly, MRD evaluation was a strong predictor of long term survival, as 3- years OS was 77.2% for MFC negative and 36.9% for double WT1 and MFC MRD positive patients, respectively, (p <0.001). Multivariate OS analysis showed that BMT year, disease status at BMT and combined MRD evaluation significantly influenced OS duration (p <0.001, <0.002 and <0.003, respectively)CONCLUSIONSPre transplant MRD evaluation by WT1 and MFC on bone marrow samples is a reliable predictor of relapse risk. Patients with both negative pre-BMT MRD markers have a significantly longer RFS, while patients with both positive MRD markers display an higher risk of relapse. Identifying patients who have an higher risk of relapse could open the way to apply pre-emptive therapeutic strategies to prevent AML relapse, from donor lymphocyte infusion to other innovative approaches. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Prognostic Value of Minimal Residual Disease Assessed By WT1 Expression Level and Flow Cytometry in Acute Myeloid Leukemia Patients Undergoing Allogeneic Marrow Transplantation

Background: Allogeneic bone marrow transplantation (BMT) offers the greatest chance of cure for most patients affected by acute myeloid leukemia (AML). Persistence of disease or high levels of pre BMT minimal residual disease (MRD) have been reported to predict disease relapse after BMT. WT1 expression levels and multicolor flow cytometry (MFC) are widely used as markers of MRD. We recently reported that combined evaluation of MRD by WT1 and MFC after induction therapy can predict relapse risk in AML patients.Aims: The aim of the present study was to apply the same MRD assessment in pre BMT setting to evaluate its reliability in predicting relapse.Methods: We retrospectively analyzed BMT outcome of 66 AML patients with both WT1-based and MFC-based MRD evaluation on bone marrow samples before transplant. Median age at transplant was 44 years. Forty-one were transplanted in first and twenty-five in second or subsequent complete remission. Induction therapies included fludarabine-containing regimens or standard ara-C and daunorubicin schedule (3+7). Median follow-up was 44 months (range 0-119 months); pre-transplantation evaluations were performed at a median of one month before transplant (range 1-3). Disease-free survival (DFS) was calculated from the time of transplantation until last follow-up or documented leukemic relapse. Overall survival was calculated from the time of transplantation to the last follow-up or death for any cause. All causes of death not directly due to relapse or progression of leukemia were considered as non-relapse mortality. A positive MFC MRD was defined by the presence of no less than 25 clustered leukemic cells /105 total events (threshold of 2.5x10-4 residual leukemic cells) at four-color flow-cytometry. Real-time PCR for WT1 was performed on DNA Engine 2 (Opticon®, MJResearch®). WT1 copy number/Abl copy number 500x104 was used as cut-off value for high WT1 expression.Results: Twenty-five relapses (37.9%) were observed. Median DFS was 31 months. Our analysis shows that the probability of relapse was significantly influenced only by disease status (first or subsequent CR) and MRD status at transplantation. Specifically, MFC-MRD was the strongest predictor of longer disease free survival (p <0.001) since no relapses occurred in the eleven MFC-MRD negative patients. Among MFC-MRD positive patients a further stratification of relapse risk is obtained by the evaluation of WT1. Patients with double positive MRD had a significantly worse DFS compared with patients who were MRD positive by MFC but MRD negative by WT1 (p <0.01). The predictive value of MRD was independent from different induction schedules; furthermore the favorable prognostic value of achieving a negative MRD status was not affected by undergoing BMT in second or subsequent remission. Median OS was 26 months and was significantly influenced by disease status and MRD status at transplantation and by relapse after BMT. Cumulative non relapse mortality was 23% at 36 months and was not associated with pre-BMT status.Conclusion: pre BMT MRD evaluation by WT1 and MFC on bone marrow samples is a reliable tool to predict relapse risk. Patients with negative pre-BMT MRD have a significantly longer DFS and OS, while MRD positive patients by both methods display a higher risk of relapse. Patients at higher risk of poor outcome should undergo a more stringent program of post BMT evaluations, in order to detect disease relapse earlier and might be candidate for pre-emptive therapeutic interventions aimed at delaying or avoiding AML reoccurrence. DisclosuresNo relevant conflicts of interest to declare.

Successful Ovarian Vitrification and Back-Transplantation to Preserve Fertility in a Patient Requiring Chemotherapy for Malignant Lymphoma

For women with hematologic malignancy anticipating chemotherapy or radio therapy but wishing to preserve fertility, it is preferable that recovery from oophorectomy be as rapid as possible. Considering Reduced-Port Surgery (RPS) to be potentially suitable for such patients, we used RPS for a patient with malignant lymphoma scheduled for pre-bone marrow transplantation chemotherapy. The patient was a 28-year-old woman, gravida 0, who had requested fertility preservation. Thus, with ethics committee approval, the left ovary was removed by RPS, and ovarian cortex with primordial ovarian follicles was cryopreserved by vitrification. The cortex was divided into 12 pieces, 1 cm×1 cm×1 mm each, placed in a container, and stored in liquid nitrogen. The patient’s post-bone marrow transplantation course was good. Because she was judged to have lost ovarian function, ovarian back-transplantation was performed by RPS. The cortex of the remaining right ovary was removed with a laparoscopic cold knife and scissors while heparin saline was instilled to maintain blood flow and a 2 cm×1 cm base was created. Two thawed ovarian cortex pieces were laparoscopically sewed to the base with 5-0 absorbable sutures. By postoperative day 173, the ovarian follicle had increased to 10 mm in diameter, and the patient’s estradiol level had risen to 101 pg/ml, suggesting recovery of ovarian function. Our experience in this lymphoma case suggests that ovarian cryopreservation and back-transplantation for fertility preservation can be performed safely by RPS and is a viable option for selected patients anticipating chemotherapy and bone marrow transplantation for hematologic malignancy.

Vitamin K deficiency in children pre-bone marrow transplantation

This study examined the prevalence of vitamin K deficiency in children pre-bone marrow transplantation (BMT). Vitamin K status was measured by the PIVKA-II assay and prothrombin times. Blood samples were obtained before vitamin-containing TPN was infused. Results indicated that eight of 26 patients (31%) were vitamin K deficient; four cases were attributed to drug antagonism (phenytoin) and four were due to inadequate vitamin K intake, synthesis or malabsorption. Only one patient had a prolonged prothrombin time. Prothrombin time, in our study, is shown to be an ineffective screening tool to determine vitamin K status. All patients receiving phenytoin and chemotherapy are at increased risk of vitamin K deficiency.

Value of panoramic radiographs in paediatric pre-bone marrow transplantation oral evaluation

Abstract.Panoramic radiographs (orthopantomogram [OPT]) are, beside clinical examination, helpful in detecting possible dental foci of infections before bone marrow transplantation (BMT). The value of an OPT in paediatric BMT-recipients was assessed by the results of dental evaluation, consisting of an OPT and a consultation by an oral surgeon, in 161 children between 1987 and 1999. Eleven out of 161 children had at least one oral focus of infection that required treatment before myeloablative therapy. In seven children the foci were detectable both clinically and radiographically and in two children the foci were visible only clinically. Only two children had a focus that was only detectable by means of radiographs. In both patients it concerned erupting third molars. In conclusion, we recommend an OPT only when the child has clinically obvious abnormalities. In addition, in older children an OPT will be indicated to evaluate the third molars.

Predictive value of host-specific donor helper T-cell precursor frequency for acute graft-versus-host disease and relapse in HLA-identical siblings receiving allogeneic bone marrow transplantation for hematological malignancies.

Acute graft-versus-host disease (aGVHD) is still one of the main causes of morbidity and mortality after allogeneic bone marrow transplantation. Attempts to avoid GVHD are associated with an increased risk of relapse, probably because the graft-versus-leukemia effect is also abrogated. It was recently suggested that a high frequency of host-specific donor helper T cell precursors (HTLp) might be predictive of significant aGVHD (grade > or = II). We retrospectively studied the frequency of HTLp by means of simplified limiting-dilution analysis to determine its predictive value for aGVHD and relapse. Pre-bone marrow transplantation, host-specific donor HLTp frequencies were analyzed in 32 patients who had received marrow from HLA-identical siblings for hematological malignancies, in terms of aGVHD and relapse. HTLp frequencies were significantly higher in patients who had aGVHD > or = grade II (n=14) than in those without aGVHD (n=18) (P=0.007). Patients who relapsed (n=13) had significantly lower HTLp frequencies than those who did not relapse (n=19) (P<0.0001). The probabilities of relapse (Kaplan-Meier method) when the HTLp frequency was higher and lower than 1/200,000 were 0% and 88%, respectively (P<0.0001). The definition of HTLp cut-off values predictive of aGVHD and relapse should contribute to donor selection and could open the way to protocols adapting immunomodulation to the likely risk of aGVHD and relapse.

Impaired liver function tests in patients treated with antithymocyte globulin: implication for liver transplantation.

Antithymocyte globulin (ATG) is traditionally used as a conventional immunosuppression agent in various pathological states including severe aplastic anaemia (SAA), graft versus host disease (GVHD), and for the prevention and treatment of graft rejection and GVHD post bone marrow and liver transplantation. We reviewed the liver functions of 16 haematological patients with no previous liver disorders who received ATG as part of their pre-bone marrow transplantation (BMT) conditioning regimen, and the liver function tests of five SAA patients who received ATG as part of their treatment. Liver functions were evaluated at day -1 pre-, and days +3 and +10 post-ATG treatment. All patients had normal liver functions before treatment. In the haematological patients, the mean serum lactic dehydrogenase (LDH) levels increased from 408.7 +/- 37.7 U/l pre-treatment to 1394.4 +/- 488.7 U/l 3 days post-treatment (n = 16; p < 0.029), and then declined to 561.4 +/- 61.3 U/l 10 days post-treatment (n = 16; p < 0.043). The mean alanine aminotransferase (ALT) levels increased from 51.9 +/- 11.3 U to 184.6 +/- 74.6 U (n = 16; p < 0.036), and then declined to 121.9 +/- 61.3 U (n = 16; NS). The mean aspartate amino transferase (AST) levels increased from 31.2 + 5.7 U to 152.0 +/- 67.0 U (n = 16; p < 0.44) and then declined to 46.0 +/- 14 (n = 16; p < 0.049). The mean tau-glutamyltransferase (GTP) levels increased from 93.0 +/- 34 to 188.0 +/- 36 (n = 16; p < 0.02), and were 168.0 +/- 37.0 at day +10 (n = 16; NS). The mean bilirubin levels increased from 18.0 +/- 1.9 microM l(-1) to 22.7 +/- 2.8 (n = 16); NS), at day +3 and to 31.9 +/- 6.9 at day +10 (n = 16; NS). In contrast, no significant changes in liver function tests were demonstrated in the SAA patients treated with ATG. The possible pathophysiologic mechanisms and the clinical implications for liver transplantation are discussed.

Adoptive transfer of immunity to hepatitis B virus after T cell–depleted allogeneic bone marrow transplantation

Recipients of allogeneic bone marrow transplantation are pancytopenic for several weeks and immunosuppressed for many months as a result of myeloablative therapy required to eliminate the basic disease and to prevent allograft rejection. After bone marrow transplantation, these patients remain profoundly immunosuppressed by the chemotherapy and immunotherapy used as prophylaxis against graft-vs.-host disease, treatment of established disease or both. These patients are usually dependent on multiple blood products and are therefore at risk for hepatitis B virus infection, which may run a fulminant course. Active immunization against hepatitis B virus in the immediate pre-bone marrow transplantation and post-bone marrow transplantation periods was found to be ineffective, probably because of the absence of T cell-dependent B-cell responses, which persists for approximately 1 yr after bone marrow transplantation. We studied adoptive transfer of immunity to hepatitis B virus through bone marrow transplantation in two populations of patients. The first group (A) consisted of 12 pairs of BMT donors and recipients, in which all bone marrow donors were positive for antibodies to HBc and HBs as a result of previously acquired hepatitis B virus infection and resolution; all recipients were negative to antibodies to HBc and HBs. The second group (B) consisted of eight pairs of donors and recipients in which all the donors were actively immunized against hepatitis B virus before bone marrow transplantation; all recipients were negative for all hepatitis B virus markers. All bone marrow transplantation recipients were monitored for antibodies to hepatitis B virus antigens.(ABSTRACT TRUNCATED AT 250 WORDS)

Anti-emetic efficacy & tolerability of tropisetron in patients (PTS) conditioned with high dose chemoradiotherapy (HDC) pre-bone marrow transplantation (BMT)

Anti-emetic efficacy & tolerability of tropisetron in patients (PTS) conditioned with high dose chemoradiotherapy (HDC) pre-bone marrow transplantation (BMT)